1Health Management Center, Naruto University
of Education, Tokushima, Japan; 2Department of
Morphological Laboratory Science, Major in Laboratory Science,
School of Health, 3Department of Laboratory of
Medicine, and 4Department of Medicine and Bioregulatory
Sciences, The University of Tokushima School of Medicine,
Tokushima, Japan
Abstract:The recent treatment of hematological malignancies
appears to be unsatisfactory in child and adult patients
with acute myeloid leukemia and adult patients with acute
lymphocytic leukemia. A major problem in the treatment of
leukemia is caused by the development of drug resistance
to chemotherapeutic agents, which is already present at
diagnosis or after chemotherapy as a minimal residual disease,
their resistance having originated from genetic or epigenetic
mutations during prior growth of the leukemia clone. It
was suggested that the mechanisms of drug resistance consist
of drug resistance proteins, which work as a drug efflux
pump. These are the permeability- related glycoprotein (P-
Gp), the multidrug-resistance associated protein (MRP),
the lung resistance protein (LRP), and other MDR proteins
such as the transporter associated with antigen processing
(TAP), anthracyclin resistance associated protein (ARA),
MRP2-7, and breast cancer resistance protein (BCRP). In
addition, anti-apoptosis mechanisms, alterations of tumor
suppressor genes, altered immunogenicity, drug resistance
mechanisms for individual drugs, and clinical risk factors
such as white blood cell count, age, and other factors have
been reported to act in drug resistance singly or in combinations.
Here we describe the update of research on the biology of
MDR in the hematological malignancies and also discuss how
to overcome MDR and adapt the updated treatment methods
in the clinical medical field. J. Med. Invest. 50:126-135,
2003
Keywords:multidrug resistance, MDR, hematology, leukemia,
lymphoma
INTRODUCTION
The recent treatment of hematological malignancies reported
that the event free survival (EFS) of children with acute
lymphocytic leukemia (ALL) was approxi-mately 75% after
reaching complete remission in more than95%. The long-term
survival for adults with ALL is only 20% after a complete
remission rate of 80%. In childhood acute myeloid leukemia
(AML), 85% reach complete remission, but EFS is only 35
-50% after remission induction therapy. The EFS of adult
patients with AML will not exceed 20% after about 85% of
the patients reach complete remission (1-3). Despite the
progress of the treatment for leukemia in recent decades,
long term survival as shown in Table1remains unsatisfactory.
A major problem in the treatment of leukemia is caused by
the development of drug resistance to chem-otherapeutic
agents. It has been observed that a biphasic decline in
the number of leukemia cells occurs during induction or
re-induction chemotherapy after relapse (4). A schematic
model is shown in Figure 1, where the biphasic decline of
leukemia cell number suggests that most leukemia cells are
sensitive to treatment and are quickly killed, leaving behind
a minor but substantial population of drug-resistant cells.
A part of the fraction called minimal residual disease may
eventually develop the drug-resistant subpopulations (4,
5). The most likely explanation for this phenomenon is that
drug-resistant cells are already present at diagnosis, their
resistance having originated from genetic or epigenetic
mutations during prior growth of the leukemia clone. The
patient whose white blood cell number is more may have more
mutated cells or drug resistant subpopulations.
There are several factors that form drug resistance mechanisms
against cytotoxic drugs in leukemia cells. It was suggested
that mechanism of drug resistance consists of drug efflux
pump, anti-apoptosis mechanism, alterations of tumor suppressor
genes, altered immunogenicity, drug resistance mechanisms
for individual drugs, and clinical risk factors such as
white blood cell counts, age, and others. Such defense mechanisms
of leukemia cells to anti - cancer drugs develop singly
or in combinations. These factors that can consist of drug
resistance mechanisms are summarized in Figure2.
CELLULAR ACTION SITES OF MECHANISMS OF DRUG RESISTANCE.
The term multidrug resistance (MDR) describes the observation
that tumor cell lines can become cross-resistant to another
structurally unrelated chemo-therapeutic agent after exposure
to a single cytotoxic drug. This is one of the major impediments
in cancer treatment, which can be caused by alterations
in drug transport, altered intracellular drug targets, altered
apoptosis mechanisms, or altered metabolic mechanisms. As
shown in Figure 3, three proteins that are related to the
alteration of drug transport are found. One is the drug
resistance protein, permeability-related glycoprotein (P-
Gp)(6, 7), and the other factor is the multidrug-resistance
associated protein (MRP)(8, 9). The third is the lung resistance
protein (LRP) found in the cytoplasm of tumor cells showing
MDR phenotype(10, 11). There are other MDR proteins such
as the transporter associated with antigen processing (TAP)(12,
13), anthracyclin resistance associated protein (ARA)(14),
MRP2-7 (15, 16), and breast cancer resistance protein (BCRP)(17,18),
although their functions have not been fully elucidated.
CHARACTERISTICS OF THE PERMEABILITY-RELATED GLYCOPROTEIN
(P-GP).
As summarized in Table 2, P- Gp is encoded by the mdr-1
gene, localized at 7q21.1, a170kDa trans-membrane glycoprotein
consisting of two domains. Up-regulation of this protein
results in a decreased intracellular concentration of anti
- cancer drugs such as anthracyclins, epipodophylotoxins,
and vinca - alkaloids. The mdr-1gene is differently expressed
in a variety of normal tissues, particularly along the apical
surface of secretory epithelium of the liver, pancreas,
jejunum and colon, proximal tubular epithelium, and the
glandular epithelium of the pregnant uterus, furthermore,
it was also reported in the adrenal grand, placenta, capillary
endothelium of the liver, testis and brain, in addition
to hematopoietic precursors and lymphocytes (6, 19).Although
the normal physiological function of P-Gp remains unknown,
P-Gp exerts its action to reduce intracellular drug accumulation,
which causes MDR as a result of the initial stage of the
therapy or due to the chemotherapy after relapses. At the
cellular level, the function of P-Gp has been extensively
investigated in many types of cancer cells. In leukemia
patients, cellular drug resistance profiles determined in
vitro at the time of presentation showed a strong correlation
with the outcome (18, 21, 22).
CHARACTERISTICS OF THE MULTIDRUG RESISTANCE ASSOCIATED
PROTEINS (MRPs).
The characteristics of seven types of MRPs that have been
found so far are shown in Table 3. MRP1 was identified in
cell lines showing a typical MDR phenotype without elevated
P-Gp. MRP is a 190 kDa protein and is encoded by the mrp
gene, located at 16p13.1 (8). MRP possesses the characteristic
structural motifs of P-Gp, and like P- Gp it is a member
of the ABC-transporter superfamily. The amino acid homology
between P-Gp and MRP1 is15%. MRP1has been detected in all
human tissues and in all cell types from peripheral blood.
Levels of MRP1 are low only in erythrocytes and liver canaliculi
(20). Although this is a transmembrane protein, anti-MRP
antibodies stain mainly the intracellular epitopes. The
physiological role of MRP1 in addition to another types
of MRPs is unknown, but inside - out plasma membrane vesicles
isolated from MRP1- overexpressing cells show an increased
ATP-dependent transport of glutathione S-conjugates in addition
to gluconate and sulphate conjugates(9). Evidence that intact
cells require glutathione (GSH) for extrusion of several
drugs by MRP1 has been obtained(9). Like P- Gp, MRP1 is
involved in altered drug distribution within intracellular
components in cytoplasm, leading to altered concentrations
of cytoplasmic drugs at their target sites(20).
CHARACTERISTICS OF LUNG RESISTANCE PROTEIN (LRP).
LRP was initially identified in an anthracyclin-resistant,
non-small cell type of lung cancer cell line which was characterized
as an MDR-phenotype but which lacked P- Gp expression (10).
As summarized in Table 4, the lrp gene was located at chromosome16p13.2,
proximal to the MRP gene on chromosome(21). LRP is a110
kDa protein and is a member of vault protein family of ribonucleoproteins,
where it is the major human vault protein, accounting for
more than 70% of the mass of vault particles. LRP is expressed
in normal hemopoietic cells and leukemia cells. LRP is not
an ABC-transporter protein, although it is involved in transmembrane
transporter of various substrates. The main function still
needs to be identified, but the main target site of LRP
may be intracellular and associated with the transport of
drugs into and out of the nucleus since vaults are colocalized
in the nuclear membrane and vesicles. Like P-Gp and MRP,
it has been suggested that LRP in normal tissues play a
role in the detoxication process (20).
METHODS IN THE DETECTION OF MDR PROTEINS.
To detect MDR expressions, there are several different methods
to use such as in situ hybridization (ISH),PCR, RT-PCR,
RNase protection, immunocytochemistry, flow cytometry, and
functional assays combined with different types of inhibitors.
These methods can detect the expressions of cellular or
tissue DNA or mRNA , or proteins. On the other hand, functional
assays using a test substance for each protein can measure
retention or accumulation of anti-cancer drugs. The following
detection methods, monoclonal antibodies, substrates for
functional assays, and inhibitors are summarized in Table5.
EXPRESSION OF MDR PROTEIN IN HEMATOLOGICAL MALIGNANCIES.
Several studies reported the frequency of the mdr-1phenotype
to be about 30 to 50% in AML patients with a higher percentage
in older patients and in patients whose leukemia relapsed
after refractory chemotherapy(21-23). No P- Gp expression
in acute promyelocytic leukemia has been found (24). In
lymphoid malignancies such as non-Hodgkin's lymphoma (NHL),
multiple myeloma (MM), chronic lymphocytic leukemia (CLL),
and adult T- cell leukemia/lymphoma (ATL), MDR-phenotypes
have been reported. Detectable levels of P-Gp range widely
from 0 to 50% in samples of NHL (25, 26). In de novo MM
patients no elevated P-Gp expression has been found in the
levels of either mRNA or protein stained with the anti-P-Gp
antibodies. However, after exposure to vincristine, adriamycin,
and dexamethazone (VAD) chemotherapy, the expression of
mdr-1 reaches levels above detectable to75%, and reaches100%
in refractory patients (27). However, because of various
subtypes of the disease in NHL, CLL, and ATL, the expression
already varies widely, making it difficult to decide on
the significance of any MDR-phenotypes. Some of this validation
can be accounted for by the threshold that was used to consider
a sample positive for P-Gp. The expression level of the
MDR protein in hematological malignancies is shown in Table
6.
Therefore, it is difficult to compare MDR expressions in
cell lines and clinical samples from different studies.
The difference in the results between studies is caused
by the different detection methods such as immunocytochemistry,
flow cytometry, RNase protection assays, and quantitative
PCR, use of different thresholds for positivity, use of
different monoclonal antibodies, comparison of different
expression levels among DNA/RNA/Protein, use of different
internal controls, and differences in methods employed to
purify leukemic blasts. In addition to these differences,
clinical prognostic factors such as white blood cell number,
age, cytogenetics, and gender in some types of malignancy
might be significant. In addition, to explain the cause
of discrepancy between studies, some studies suggested the
presence of a non-functional drug efflux pump among the
MDR proteins and unknown proteins that can function as MDR
phenotypes.
PROGNOSTIC SIGNIFICANCE OF MDR PHENOTYPES AT DIAGNOSIS
IN HEMATOLOGICAL MALIGNANCIES.
In AML, most of the study found that mdr-1over-expression
at diagnosis is a strong impediment predictor for complete
remission and long-term survival, although there is a suggestion
of a different “behavior" between adult and childhood
AML (21, 22, 28). In childhood AML, P-Gp is not associated
with a poor prognosis (28). This is controversial, but there
is a correlation between clinical outcome of AML and MRP1
or LRP. Studies on LRP in AML emphasized the importance
of the correlation between LRP-expression and anthracyclin
accumulation and suggested that LRP-expression has a prognostic
value at diagnosis(29, 30). However, there is an equal number
of studies where a predictive value in the case of LRP-
expression in de novo AML cannot be shown (31, 32). Co -
expression of P-Gp and MRP has also been associated with
poor outcome in AML (29, 33).
In ALL, mdr-1expression is of minor importance for prediction
of outcome, and MRP1expression at diagnosis is not associated
with response and long term survival. The prognostic significance
of LRP expression in ALL is still controversial between
positive and negative results (21).
There is a number of studies on the incidence of P- Gp expression
in NHL. P- Gp expression has been correlated with drug sensitivity
and clinical outcome in NHL. However, other studies did
not find a correlation between response and P-Gp expression.
Thus, it is presently unclear whether MDR expression has
a significant impact on the response to therapy in lymph-oma
(25, 27).
In de novo MM patients P- Gp expression does not appear
to occur, since myeloma cells at diagnosis neither express
elevated levels of mdr-1mRNA nor stain with the anti-P-Gp
antibodies (34). MRP is not over- expressed in MM, but LRP
is expressed in half of the MM patients, and is associated
with a poor response to melphalan at conventional doses
(35).
Most of these studies recognized the increased expression
level in leukemia cells of relapsed or of the refractory
stage compared with cells at diagnosis. The prognostic significance
of MDR phenotypes at diagnosis in hematological malignancies
is summarized in Table 7.
ROLE OF THE APOPTOSIS CASCADE THROUGH
DEATH RECEPTORS IN HEMATOLOGICAL MALIGNANCIES.
To bring about cell death through death receptors and apoptosis
cascade proteins, there are two routes : either through
mitochondrial or through non-mitochondrial paths, as summarized
in Figure 4. As it is well known, cell death through the
non-mitochondrial apoptosis cascade begins at receptor sites
such as Fas (CD95/Apo-1), TRAIL-R, and tumor necrosis factor
receptor (TNF-R) on the cell membrane by binding the ligands
of each receptor or by granzyme B. The receptor-ligand binding
activates downstream caspases, leading to the subsequent
cleavage of death substrates. These substrates can eventually
cause DNA fragmentation. It is well known that bcl-2and
survivin (c-IAP1/2)work as inhibitors for this pathway.
P-Gp protects leukemia cells against caspase-dependent,
but not caspase-independent cell death (36). Anti -P- Gp
antibody induced Fas antigen in PBMC and accelerated apoptosis
through Fas-Fas-ligand interaction (37).
Alterations of apoptosis cascade genes associated with drug
resistance have been found in studies using cell lines or
fresh cells. Over- expression of bcl -2 with MAPK pathway
links to drug resistance in AML (38). The constitutive expression
level of Fas and bcl -2 is important, and the expression
of these antigens is a predictive factor of the chemosensitivity
in leukemia, especially in AML, though not in ALL (39, 40).
Low or alteration of Fas expression leads to refractoriness
in T-cell type ALL or normal T lymphocytes (41). Blocking
of caspase 8 results in TRAIL resistance, and increased
NF-κB can inhibit apoptosis in MM cells (42).
Heat shock protein (HSP) 90 inhibits apoptosis in mononuclear
phagocytic cells (43).
ALTERATIONS OF TUMOR SUPPRESSOR GENES ASSOCIATED WITH
DRUG RESISTANCE.
Among quite a few tumor suppressor genes, WT1 was found
as a tumor suppressor gene in childhood Wilms' tumor, which
is located at chromosome 11 at band p13. The WT1 gene encodes
a zinc finger transcription factor, which binds to GC-rich
sequences and functions as a transcriptional activator or
repressor for many genes. The WT1 protein is mainly expressed
in cells or tissues of the genitourinary system. It is well
known that its over- expression links to poor prognosis
in leukemia. On the other hand, p53was found at chromosome
17p13, which is activated or increased by injury in DNA
or by stress, resulting in G1 arrest or apoptosis. P53 alteration
including mutation was reported in various types of hematological
malignancies such as CML, NHL, AML, and ALL (44, 45). No
link has been found between the abnormality of the RB gene
and drug resistance in hematological malignancy.
Mdm2 and ras genes are oncogenes. Mdm2 is activated by the
induction of p53 and inactivates the functions of p53, which
inhibits p53 induced G1 arrest and apoptosis. It was reported
that mdm2 over-ex-pression often associates refractoriness
in ALL (46, 47).The Ras gene causes immortalization or transformation
of cells by associating with c-myc or p53. Thus, it was
reported that a ras mutation leads to lowered mdr-1in adult
T-cell leukemia (48).
In the future, a therapy that attacks the altered ex-pression
of the apoptosis cascade, aimed at tumor suppressor genes,
and in combination with conventional drugs may be promising.
REVERSAL OF DRUG RESISTANCE.
Two possible approaches to mdr-1 reversal by agents can
be distinguished. The first option is the use of modulating
agents that can restore drug accumulation by competing with
cytostatic drugs for P- Gp binding sites. These agents include
calcium channel blockers, some type of cardiovascular drugs,
cyclosporin analogs, and anti-malarias. When initially trying
to overcome MDR, we found that an anti-platelet drug, dipyridamole,
could overcome MDR in leukemia cells (49, 50). Subsequently,
more substances have been tested and found to counteract
MDR. We found that the activity of MRP1can be blocked by
a variety of chemical compounds, where the effect of P-Gp
modulators on MRP1 was less than their effect on P-Gp over-expressing
cells(51). Although the results of the few studies with
P-Gp modifiers in the hematological malignancies are promising,
the data are insufficient for recommending the routine use
of such drugs to increase disease-free survival in leukemia.
Most of these agents produced severe toxic effects at doses
required to effectively block P- Gp function, and modulation
of P- Gp in normal tissues can affect the pharmacokinetics
and, thus, the toxicity of the associated chemotherapeutic
agents(52). So far, clinical intervention studies with mdr-1modifying
agents have only been done with AML patients using a modified
analog to cyclosporin D, PSC833 (valspodar). Such third
generation MDR modulators can be safely administered in
combination with different chemotherapy regimens after a
dose adjustment of cytotoxic drugs that are P-Gp substrates
(53).
In addition, some agents such as mdr-1- specific anti -sense
oligonucleotides and protein kinase C inhibitors such as
staurosporin have been demonstrated to be capable of down-regulating
mdr-1 expression (54, 55).
Secondly, immunotherapy against a surface antigen of the
membrane of leukemia cells may be promising(56). We confirmed
the efficacy to be 5-fold higher the wild-type cell line
of mouse human chimeric anti-CD20antibody on the VCR-resistant
cell line of Daudi, an endemic Burkitt's lymphoma cell line,
in which the expression level of CD20 remained unchanged
compared with those in the wild-type cells. In contrast,
however, the anti- CD20 antibody was ineffective in a VCR-resistant
BLTH, a non-endemic Burkitt's lymphoma cell line, in which
CD20 disappeared (57). Thus, it was suggested that the resistance
to VCR in some tumor cell lines is associated with a modified
antigen expression of the target molecule and susceptibility
to immunotherapies.
Active oxygen radicals can damage the cell membranes by
oxidizing their lipids. By such cytotoxic activity of oxygen
radicals certain antineoplastic agents such as adriamycin,
bleomycin, and etoposide exert their efficacy. Consequently,
we found the cross-resistance in VCR-resistant cells with
increased P-Gp and MRP expression to oxygen radicals which
was produced by the hypoxanthin-xanthin oxidase reaction(58).
Increased resistance to oxygen radicals may be caused by
an altered membrane structure in VCR-resistant cells, being
an impediment to treatment. These results may suggest a
new mechanism of drug resistance in cells expressing P-Gp
(59).
FUTURE DIRECTION OF THERAPY TO OVERCOME MULTIDRUG RESISTANCE.
Clinical trials of the modulation of MDR have been limited
by two major factors : the inability of achieving adequate
blood levels of the modulator to reverse MDR in patients,
and the presence of other resistance mech-anisms in addition
to P- Gp. A third factor is that P- Gp modulators alter
the pharmacokinetics of anti-cancer drugs by delaying their
elimination : this can potentially increase toxicities if
the dose of anticancer drugs is not appropriately reduced.
However, because it was demonstrated that MDR modulators
such as valspodar show substantial inhibition of P- Gp,
reversal agents that only inhibit P-Gp in tumor cells and
do not influence the pharmacokinetics of cytotoxic agents
should be developed. Thus, to explore the potential of transporter-specific
modulators in improving clinical outcome, more knowledge
will be needed on the nature, substrate spe-cificity, inhibitory
sensitivity, and expression of the efflux pump responsible
for MDR in human cancer.
The current therapy needs too high doses of anti-cancer
agents to overcome drug resistance and often cause severe
adverse effects, resulting in over-treatment. To avoid such
over-treatment or under-treatment, the following is recommended;
? identification of the type of drug resistance in each
patient.
?evaluation of chemo-sensitivity of a patient's normal cells
or tissues in addition to those of malignant cells against
anti-cancer drugs.
?determination of the treatment strategy such as dose of
drugs and schedule of chemotherapy on the basis of these
data.
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